Cancer treatments using combinations of CDK and ERK inhibitors

Abstract

The present invention provides, inter alia, methods, kits, and pharmaceutical compositions for treating or ameliorating the effects of a cancer in a subject in need thereof. The method comprises administering to the subject an effective amount of (i) a first anti-cancer agent, which is BVD-523 or a pharmaceutically acceptable salt thereof and (ii) a second anti-cancer agent, which is a CDK inhibitor or a pharmaceutically acceptable salt thereof, to treat or ameliorate the effects of the cancer. Additional methods for effecting cancer cell death are also provided.

What is claimed is: 
     
       1. A method of treating or ameliorating the effects of melanoma in a subject having a somatic NRAS mutation, comprising administering to the subject an effective amount of (i) a first anti-cancer agent, which is BVD-523 or a pharmaceutically acceptable salt thereof and (ii) a second anti-cancer agent, which is LEE-011 or a pharmaceutically acceptable salt thereof, wherein administration of the first and second anti-cancer agents provides a synergistic effect compared to administration of either anti-cancer agent alone. 
     
     
       2. The method of  claim 1 , wherein the subject is a mammal. 
     
     
       3. The method of  claim 2 , wherein the mammal is selected from the group consisting of humans, primates, farm animals, and domestic animals. 
     
     
       4. The method of  claim 2 , wherein the mammal is a human. 
     
     
       5. The method of  claim 1 , further comprising administering to the subject at least one additional therapeutic agent selected from the group consisting of an antibody or fragment thereof, a toxin, a radionuclide, an immunomodulator, a radiosensitizing agent, a hormone, an anti-angiogenesis agent, and combinations thereof. 
     
     
       6. The method of  claim 5 , wherein the at least one additional therapeutic agent is an antibody or fragment thereof selected from the group consisting of rituximab, Cetuximab, bevacizumab, and Ibritumomab. 
     
     
       7. The method of  claim 5 , wherein the at least one additional therapeutic agent is a toxin, which is diphtheria toxin or portions thereof. 
     
     
       8. The method of  claim 5 , wherein the at least one additional therapeutic agent is a radionuclide selected from the group consisting of I-125, At-211, Lu-177, Cu-67, I-131, Sm-153, Re-186, P-32, Re-188, In-114m, and Y-90. 
     
     
       9. The method of  claim 5 , wherein the at least one additional therapeutic agent is an immunomodulator selected from the group consisting of granulocyte colony-stimulating factor (G-CSF), interferons, imiquimod and cellular membrane fractions from bacteria, IL-2, IL-7, IL-12, CCL3, CCL26, CXCL7, and synthetic cytosine phosphate-guanosine (CpG). 
     
     
       10. The method of  claim 5 , wherein the at least one additional therapeutic agent is a radiosensitizing agent selected from the group consisting of misonidazole, metronidazole, tirapazamine, and trans sodium crocetinate. 
     
     
       11. The method of  claim 5 , wherein the at least one additional therapeutic agent is a hormone selected from the group consisting of prostaglandins, leukotrienes, prostacyclin, thromboxane, amylin, antimullerianormone, adiponectin, adrenocorticotropic hormone, angiotensinogen, angiotensin, vasopressin, atriopeptin, brain natriuretic peptide, calcitonin, cholecystokinin, corticotropin-releasing hormone, encephalin, endothelin, erythropoietin, follicle-stimulating hormone, galanin, gastrin, ghrelin, glucagon, gonadotropin-releasing hormone, growth hormone-releasing hormone, human chorionic gonadotropin, human placental lactogen, growth hormone, inhibin, insulin, somatomedin, leptin, liptropin, luteinizing hormone, melanocyte stimulating hormone, motilin, orexin, oxytocin, pancreatic polypeptide, parathyroid hormone, prolactin, prolactin releasing hormone, relaxin, renin, secretin, somatostain, thrombopoietin, thyroid-stimulating hormone, testosterone, dehydroepiandrosterone, androstenedione, dihydrotestosterone, aldosterone, estradiol, estrone, estriol, cortisol, progesterone, calcitriol, calcidiol, tamoxifen, anastrozole, letrozole, and fulvestrant. 
     
     
       12. The method of  claim 5 , wherein the at least one additional therapeutic agent is an anti-angiogenesis agent selected from the group consisting of 2-methoxyestradiol, angiostatin, bevacizumab, cartilage-derived angiogenesis inhibitory factor, endostatin, IFN-α, IL-12, itraconazole, linomide, platelet factor-4, prolactin, SU5416, suramin, tasquinimod, tecogalan, tetrathiomolybdate, thalidomide, thrombospondin, thrombospondin, TNP-470, ziv-aflibercept, pharmaceutically acceptable salts thereof, prodrugs, and combinations thereof. 
     
     
       13. A method of effecting cancer cell death comprising contacting the cancer cell with an effective amount of (i) a first anti-cancer agent, which is BVD-523 or a pharmaceutically acceptable salt thereof and (ii) a second anti-cancer agent, which is LEE-011 or a pharmaceutically acceptable salt thereof, wherein the cancer cell is obtained from a subject with melanoma having a somatic NRAS mutation, and wherein administration of the first and second anti-cancer agents provides a synergistic effect compared to administration of either anti-cancer agent alone. 
     
     
       14. The method of  claim 13 , wherein the subject is a mammal. 
     
     
       15. The method of  claim 14 , wherein the mammal is selected from the group consisting of humans, primates, farm animals, and domestic animals. 
     
     
       16. The method of  claim 14 , wherein the mammal is a human. 
     
     
       17. The method of  claim 13 , further comprising contacting the cancer cell with at least one additional therapeutic agent selected from the group consisting of an antibody or fragment thereof, a toxin, a radionuclide, an immunomodulator, a radiosensitizing agent, a hormone, an anti-angiogenesis agent, and combinations thereof. 
     
     
       18. The method of  claim 17 , wherein the at least one additional therapeutic agent is an antibody or fragment thereof selected from the group consisting of rituximab, Cetuximab, bevacizumab, and Ibritumomab. 
     
     
       19. The method of  claim 17 , wherein the at least one additional therapeutic agent is a toxin, which is diphtheria toxin or portions thereof. 
     
     
       20. The method of  claim 17 , wherein the at least one additional therapeutic agent is a radionuclide selected from the group consisting of I-125, At-211, Lu-177, Cu-67, I-131, Sm-153, Re-186, P-32, Re-188, In-114m, and Y-90. 
     
     
       21. The method of  claim 17 , wherein the at least one additional therapeutic agent is an immunomodulator selected from the group consisting of granulocyte colony-stimulating factor (G-CSF), interferons, imiquimod and cellular membrane fractions from bacteria, IL-2, IL-7, IL-12, CCL3, CCL26, CXCL7, and synthetic cytosine phosphate-guanosine (CpG). 
     
     
       22. The method of  claim 17 , wherein the at least one additional therapeutic agent is a radiosensitizing agent selected from the group consisting of misonidazole, metronidazole, tirapazamine, and trans sodium crocetinate. 
     
     
       23. The method of  claim 17 , wherein the at least one additional therapeutic agent is a hormone selected from the group consisting of prostaglandins, leukotrienes, prostacyclin, thromboxane, amylin, antimullerianormone, adiponectin, adrenocorticotropic hormone, angiotensinogen, angiotensin, vasopressin, atriopeptin, brain natriuretic peptide, calcitonin, cholecystokinin, corticotropin-releasing hormone, encephalin, endothelin, erythropoietin, follicle-stimulating hormone, galanin, gastrin, ghrelin, glucagon, gonadotropin-releasing hormone, growth hormone-releasing hormone, human chorionic gonadotropin, human placental lactogen, growth hormone, inhibin, insulin, somatomedin, leptin, liptropin, luteinizing hormone, melanocyte stimulating hormone, motilin, orexin, oxytocin, pancreatic polypeptide, parathyroid hormone, prolactin, prolactin releasing hormone, relaxin, renin, secretin, somatostain, thrombopoietin, thyroid-stimulating hormone, testosterone, dehydroepiandrosterone, androstenedione, dihydrotestosterone, aldosterone, estradiol, estrone, estriol, cortisol, progesterone, calcitriol, calcidiol, tamoxifen, anastrozole, letrozole, and fulvestrant. 
     
     
       24. The method of  claim 17 , wherein the at least one additional therapeutic agent is an anti-angiogenesis agent selected from the group consisting of 2-methoxyestradiol, angiostatin, bevacizumab, cartilage-derived angiogenesis inhibitory factor, endostatin, IFN-α, IL-12, itraconazole, linomide, platelet factor-4, prolactin, SU5416, suramin, tasquinimod, tecogalan, tetrathiomolybdate, thalidomide, thrombospondin, thrombospondin, TNP-470, ziv-aflibercept, pharmaceutically acceptable salts thereof, prodrugs, and combinations thereof.